Unique aspects of the biology of HIV/SIV infection, including the use of immunologically functional CD4 as the receptor for infection of functional immune cells, the permanence of the infection due to integration into the host genome, and the mutability of these viruses pose great challenges for the development of a protective vaccine. Since a dominant protective immune mechanism remains unidentified, several potentially protective immune mechanisms must be considered and intensively studied simultaneously in order to fully understand the results of vaccine trials. Sexual transmission of cell-free an cell- associated virus to mucosal membranes is a major route of infection. Studies of mucosal immunity pose a particular problem because the process of mucosal infection and the mechanisms of immunity are not completely understood. Such studies are labor intensive and technically demanding, and require groups with diverse skills for their accomplishment. Two on- site groups will work in close collaboration to provide a comprehensive evaluation of systemic and mucosal immunity related to viral pathogenesis and protection. We will: 1) define the early interactions between virus and host at the intestinal mucosa, with particular attention to the role of macrophages; 2) provide a reproducible model both to evaluate mucosal immunity and to identify infected and/or partially protected monkeys following experimental mucosal challenge; and 3) assess the mucosal immune system by immunohistochemical characterization of gut-associated lymphoid cells, cytokine expression, and measurement of humoral IgM, IgG and IgA antibodies.